Source: Nanjing Zhihe AI Research Institute | May 9, 2026 | Zhihe WeChat [R&D Frontier]

Key Takeaways

Small nucleic acid therapeutics are the third major drug modality after small molecules and antibodies, with over 300 pipelines in development globally in 2026.

Nearly 20 products are on the market; Inclisiran reached USD 1.198 billion in global sales in 2025, entering the blockbuster tier.

GalNAc conjugation is the gold standard for liver-targeted siRNA; 2026 brings the first clinical-validation milestones for extrahepatic delivery.

Chinese players such as RemeBio and Sirnaomics are catching up fast; RemeBio listed on HKEX (06938.HK) in early 2026 and is signing frequent international BD deals.

Against the backdrop of Zhihe pipelines such as BD2/DSC1008, small-nucleic-acid delivery platforms and target collaboration are becoming a strategic focus.

1. Introduction: The Third Drug Revolution Is Here

In 2023, the Nobel Prize in Physiology or Medicine was awarded to mRNA pioneers Karikó and Weissman, marking the arrival of the nucleic-acid-therapy era.

Yet beyond the spotlight of mRNA, a quieter but equally profound revolution is accelerating.

Small nucleic acid drugs, represented by siRNA and antisense oligonucleotides (ASOs), are reshaping chronic-disease and genetic-disease treatment with their "one shot, two years of precision silencing" advantage.

2026 is a milestone year for small nucleic acid drugs.

Nearly 20 products have been approved globally.

The first siRNA lipid-lowering drug Inclisiran surpassed USD 1 billion in annual sales.

RemeBio and Madrigal signed a milestone deal worth up to USD 4.4 billion, a new Chinese small-nucleic-acid BD record.

Meanwhile, GalNAc conjugation is maturing and extrahepatic delivery is hitting key clinical-validation milestones.

Small nucleic acid drugs are expanding from "liver-only" into cardiovascular, CNS, and metabolic disease.

Starting from mechanism, this article systematically reviews the technology principles, chemical modification strategies, and delivery-platform evolution of small nucleic acid drugs, with a focus on the global pipeline landscape and 2026 progress.

It concludes with strategic insight from the Zhihe BD perspective.

2. Mechanism: Silencing Disease Genes at the Post-Transcriptional Level

2.1 What Are Small Nucleic Acid Drugs

Small nucleic acid therapeutics are synthetic oligonucleotide chains typically 13 to 30 nucleotides in length.

By complementary pairing with target mRNA or pre-mRNA, they intervene in gene expression at the post-transcriptional level to exert therapeutic effects.

siRNA: double-stranded RNA of about 19-23 nt that recruits the RISC complex to cleave target mRNA, achieving efficient gene silencing.

Representatives: Inclisiran (PCSK9) and Givosiran (ALAS1).

ASO: single-stranded DNA/RNA hybrids of 13-25 nt that cleave target mRNA via RNase H or interfere with splicing/translation through steric hindrance.

Representatives: Nusinersen (SMN2 pre-mRNA splicing) and Fomivirsen.

miRNA mimics/inhibitors: mimic endogenous miRNA function or inhibit it, modulating entire gene networks.

saRNA: upregulate gene expression by targeting promoter regions, opposite to siRNA silencing.

Representatives such as MTCure are in early clinical stages.

3. Chemical Modification Strategies: Armor and Navigation

Natural RNA/DNA is rapidly degraded by nucleases in vivo, with half-lives often under minutes.

Chemical modification is the core barrier to clinical translation, with three main dimensions.

3.1 Backbone Modification

Phosphorothioate (PS): replaces non-bridging oxygens in the phosphate backbone with sulfur.

It greatly enhances nuclease resistance and increases serum-protein binding (improving tissue distribution).

Nearly all ASO products contain PS modification.

PS2: replaces both non-bridging oxygens with sulfur, more potent than PS.

Validated in next-generation siRNA to further extend in vivo half-life.

PMO: replaces ribose with morpholine, giving a fully uncharged backbone that does not activate RNase H.

Eteplirsen (for DMD) is a PMO drug.

3.2 Sugar Modification

2'-OMe: enhances duplex stability and reduces immunogenicity; widely used on siRNA strands.

It is a "must-have" for clinical-grade siRNA.

2'-F: enhances nuclease resistance and target binding.

Typically alternated with 2'-OMe on siRNA strands in an "alternating" pattern.

Alnylam's ESC (Enhanced Stabilization Chemistry) platform is built on this.

LNA: forms a methylene bridge between 2'-O and 4'-C, locking the ribose conformation and dramatically improving target affinity (Tm +3-8°C per LNA).

Common in ASOs; Roche's Nedosiran contains LNA modifications.

3.3 Targeted Delivery Modification

Ligand conjugation is the most breakthrough-style technical progress in recent years.

GalNAc (N-acetylgalactosamine) conjugation has become the "industry standard" for liver-targeted small nucleic acids.

Trivalent GalNAc-siRNA conjugate: GalNAc binds the asialoglycoprotein receptor (ASGPR) on hepatocytes with high affinity (Kd ~1 nM).

Receptor-mediated endocytosis delivers the conjugate efficiently into hepatocytes, enabling liver targeting via subcutaneous administration.

All next-generation liver-targeted siRNAs — Inclisiran, Givosiran, Lumasiran — use this strategy.

Extrahepatic delivery (frontier in 2026): improved lipid nanoparticles (LNPs) targeting lung, muscle, and CNS.

Antibody-conjugated nucleic acids (ACNA) use monoclonal antibodies for cell-type-specific delivery.

Dynamic polyconjugates (DPC) are being explored for tumor targeting.

Companies such as Arrowhead and Sirnaomics have entered Phase I/II clinical validation.

4. Global Pipeline Landscape: Three Major Battlefields

4.1 Approved Products

Nearly 20 small nucleic acid drugs have been approved globally.

They cover hATTR, hypercholesterolemia, primary hyperoxaluria, hemophilia, and other indications.

4.2 Major 2026 Clinical Updates

Inclisiran commercialization accelerates: Novartis reported 2025 sales of USD 1.198 billion, up about 80% year on year.

It crossed USD 1 billion for the first time and in May 2026 was approved for a new indication by China NMPA.

The Chinese market outlook is broad.

RemeBio x Madrigal USD 4.4 billion BD: a siRNA targeting HSD17B13 for MASH (metabolic dysfunction-associated steatohepatitis).

It is the largest single-asset small-nucleic-acid BD deal to date, highlighting MASH potential.

Alnylam HELIOS-B Phase III readout: Vutrisiran significantly reduced all-cause mortality in ATTR cardiomyopathy.

This reinforces small nucleic acids in cardiology; indication-expansion filings are expected in 2026.

ARO-INHBE (Arrowhead) completed Phase II enrollment: a siRNA targeting INHBE for obesity/metabolic syndrome.

Phase II enrollment completed in January 2026; extrahepatic effects (skeletal muscle INHBE inhibition) data are worth watching.

RBD4059 (RemeBio) advances global development: the most advanced FXI-targeting siRNA.

Its low bleeding-risk profile addresses a traditional anticoagulation pain point; Phase III is planned.

CNS small-nucleic-acid clinical year begins: Ionis' ION363 (SOD1, ALS) and Biogen's BIIB067 have validated CNS deliverability.

In 2026, multiple companies are advancing LNP/novel-exosome-based CNS nucleic-acid drugs into Phase I.

5. Strengths and Challenges: Between Vision and Reality

5.1 Core Strengths

Expanded target space: traditional small molecules can target only about 700 "druggable" proteins.

Small nucleic acid drugs act at the mRNA level and can theoretically target all protein-coding genes.

This expands the druggable target universe by roughly 10x.

Strong long-acting advantage: the catalytic cycle of RISC in hepatocytes allows a single subcutaneous dose to maintain silencing for 3-6 months.

Inclisiran even achieves "two shots a year".

Compliance advantages particularly suit chronic cardiovascular settings.

Manageable safety: targeting mRNA is reversible (target gene expression gradually recovers after dosing stops).

Compared with permanent gene editing, safety risks are easier to manage.

High platform efficiency: once the GalNAc platform is mature, swapping the sequence rapidly switches targets.

Development efficiency exceeds that of monoclonal antibodies.

Alnylam has achieved a multi-year "one new drug per year" cadence.

5.2 Remaining Core Challenges

Extrahepatic delivery remains the biggest bottleneck: GalNAc is limited to hepatocytes.

Over 80% of disease-relevant targets reside in non-hepatic tissues (brain, lung, tumor, muscle, heart, etc.).

LNPs have low extrahepatic delivery efficiency and poor organ specificity.

Novel delivery technologies remain in early validation — the largest technology gap the industry recognizes.

Immunogenicity and off-target risk: insufficient sequence specificity can cause off-target silencing.

Double-stranded siRNA can activate innate immunity (TLR7/8) and must be mitigated by modification.

ASOs carry non-sequence-specific toxicity (plasma protein binding, complement activation).

Low endosomal escape: after receptor-mediated endocytosis, about 95-99% of nucleic-acid molecules are trapped and degraded in endosomes/lysosomes.

Only a tiny fraction reaches the cytoplasm — a key scientific challenge for improving delivery efficiency.

Complex and costly manufacturing: solid-phase oligonucleotide synthesis (SPPS) is hard to scale up.

Multiple modification steps drive up purification costs, making CDMO capacity a critical bottleneck.

Regulatory pathways are still maturing: FDA, EMA, and CDE have issued oligonucleotide-specific guidelines from 2024 to 2026.

The framework is improving but uncertainty remains; CDE still has relatively limited oligonucleotide review experience.

6. Regulatory Update: Global Frameworks Maturing

FDA (November 2024): released the draft guideline on nonclinical safety evaluation of oligonucleotide therapeutics.

It clarifies immunotoxicity assessment paths, impurity standards, and off-target evaluation requirements.

EMA (July 2024): released the draft guideline on oligonucleotide chemical drug development and manufacture.

It emphasizes strict control of sequence-specific impurities (n-1, n+1 fragments).

CDE (2026 update): in its small-nucleic-acid regulatory framework, clarified that siRNA/ASO follow chemical-drug registration pathways (Category 3/Category 1 innovative drugs).

Parallel submissions with FDA/EMA are encouraged, with a positive stance on overseas data reciprocity.

Overall: regulatory improvements will significantly accelerate domestic small-nucleic-acid review timelines.

The first wave of domestic siRNA/ASO NDAs is expected in 2026-2028.

7. Summary and Outlook

Small nucleic acid drugs are transforming from "rare-disease orphans" to "mainstream chronic-disease therapies".

In 2026, this transformation is marked by Inclisiran crossing USD 1 billion, RemeBio's HKEX listing, and record global BD deals, accelerating into a golden breakout.

The core technology logic is clear: GalNAc conjugation plus chemical modification has locked down liver-targeted siRNA.

The next five years' key battle is extrahepatic delivery — whoever first solves precision delivery to the CNS, tumor microenvironment, and cardiomyocytes will hold the high ground of third-generation nucleic-acid drugs.

Disclaimer: This article is a popular-science piece by Nanjing Zhihe AI Research Institute for academic exchange only; not investment advice.

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